In 1959, spontaneous autoantibody production was discovered in New Zealand mice. Subsequent studies demonstrated a striking similarity of New Zealand black mice to patients with idiopathic-acquired hemolytic anemia and New Zealand black x white F1 hybrids to humans with systemic lupus erythematosus. Numerous experiments have indicated that genetic and/or viral interrelationships with lymphoid elements are critical for disease pathogenesis in mice. However, the precise role of the thymus and spleen and their respective subpopulations in the development of autoimmunity and lymphoproliferative disease remains unclear. It is intended to create unique animal models to resolve these issues. These models are production of congenitally athymic (nude) New Zealand black (NZB), New Zealand white (NZW) and NZBxNZW F1 mice, and New Zealand mice congenic for the Xid gene of CBA/N. The natural history and immune responsiveness of these mutant colonies will be studied and compared with littermate controls. The mechanism of polyclonal expansion of B cells and subsequent antibody production in New Zealand mice remains a critical question. We have been studying the requirements for autoantibody production both in NZB mice as well as NZB mice cogenic with the Xid gene of CBA/N mice. We have attempted to alter the immunologic phenotype of NZB.Xid mice by transfer of cells from young and old NZB mice. There was little difficulty in restoring normal levels of serum IgM, IgG3, splenic Lyb-5 cells and response to DNP-Ficoll in young NZB.Xid mice that were injected with young NZB bone marrow cells. Although such animals had an almost immediate change in their immune profile to values characteristic of NZB mice, they required, much like unmanipulated NZB mice, a latency period of an additional 6 months before autoantibodies were detected. In contrast, adult NZB.Xid mice, who likewise developed an immune profile similar to NZB after transfer of bone marrow cells from young NZB mice, began to express autoantibodies immediately without any latency period. NZB.Xid mice who were recipients of adult NZB bone marrow cells did not show sustained autoantibody production, reflecting the limited state of B-cell precursors in adult NZB mice. Thus, the age of both donor cells and the age of recipient mice are critical factors for determining the latency period and the age at which autoantibodies will appear. Similarly, we attempted to alter the production of autoantibodies in NZB mice that were irradiated and injected with bone marrow cells from NZB.Xid animals. NZB mice had a major amelioration of disease when they received cell transfers from young NZB.Xid mice. This amelioration, which included the acquisition of the immune profile of NZB.Xid animals, was not seen in adult NZB mice that were recipients of young NZB cells. We suggest that, although Lyb-5 cells may be the effective mechanism for autoantibody production, there are other interacting influences that may selectively turn on or turn off autoantibodies and that are required and are responsible for the latency period. Further, specific experiments in transplantation and cell transfer of thymus and spleen from syngeneic mice of different serial ages will be designed to identify the relationships between alterations in lymphoid subpopulations with age and development of autoimmunity and lymphoproliferative disease. (SR)